138 Drug price reforms: the new F1–F2 bifurcation (Editorial) TFaunce&HLofgren

140 Letters

142 Top 10 drugs

143 Drugs for the doctor's bag ABaird

146 Dental notes Drugsforthedoctor'sbag

147 Abnormal laboratory results: Evaluation of adrenocortical function in adults JHo&DJTorpy

150 Relationships between health professionals and industry: maintaining a delicate balance PAKomesaroff

153 Dental notes Relationshipsbetweenhealthprofessionalsandindustry

153 Medicines Australia Code of Conduct: breaches

154 The story of one complaint

156 Treatment of myasthenia gravis SWReddel

160 Dental notes Treatmentofmyastheniagravis

160 Patient support organisation

161 Myasthenia gravis: a patient's perspective

162 Antipsychotic drugs in pregnancy and breastfeeding DKennedy

163 New drugsabatacept,exenatide,telbivudine

Fulltextwithsearchfacilityonlineatwww.australianprescriber.com

VoLuME 30 NuMbER 6 AN iNDEPENDENT REViEw DECEMbER 2007 C o n T E n T S

138 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

Editorial

in this issue…

Drug price reforms: the new F1–F2 bifurcationThomas Faunce, Senior Lecturer, College of Law and Medical School, Australian National University, Canberra; and Hans Lofgren, Senior Lecturer, School of International and Political Studies, Deakin University, Burwood, Victoria

Keywords:genericdrugs,PharmaceuticalBenefitsScheme,

referencepricing.

(Aust Prescr 2007;30:138–40)

SignificantchangestothePharmaceuticalBenefitsScheme

(PBS)areunderway.TheAustralianParliamentrecentlypassed

theNational Health Amendment (Pharmaceutical Benefits

Scheme) Act 2007.AtthecoreofthisActarenewsections

(85ABand85AC)totheNational Health Act 1953.Thesehadthe

effectofdividing,from1August2007,thePBSintotwoseparate

formularies–F1,whichmostlycontainssinglebrandmedicines,

andF2,whichmostlycontainsmultiplebrand,mainlygeneric,

medicines(seebox).

Thesecomplexchangesaimto'recognisetheimportanceof

world-classlife-enhancingdrugstopatients',protectpatients

fromhighercostsandgetbettervaluefrommarketcompetition

betweenmedicineswithmultiplebrands.1Thechangesmay

allowPBSandpatientsavingsthroughlowerpricedgenerics,

buttheirimpactonthepriceofpatentedsingle-brandmedicines

isuncertaininourview.Chieflythisisbecauseinfuturemost

newpatentedmedicineswillbelistedinF1withreduced

referencepricingthereafter.

InAustralia,overallpharmacyfeesvaryforproductspriced

belowthegeneralpatientco-payment($30.70),andaChoice

surveyinAugust2006foundawiderangeintheprices

pharmaciescharge.2Thiswasduetovariedapplicationof

permissiblefeesundertheFourthCommunityPharmacy

Agreement.Australianpricesforgenericdrugswerehigher

thanincountrieswithlargermarketsorprocessessuchas

competitivetender.InAustralia,thepriceapatientpaidfor

amedicinebelowthegeneralco-paymentdependedonthe

manufacturer'sprice,wholesaleandpharmacymarkups,and

dispensingfees.Manufacturerscouldoffergenericdrugsto

pharmacistsatlargediscountstothepricespaidbythePBS.

Thegovernmentthereforeconsideredthatithadbeenpaying

toomuchforthesemedicines.Inourview,thisconsideration

unfortunatelyoutweighedpolicyconcernsabouttheimportance

ofmaintainingthefullintegrityofPBSreferencepricing.1,3

PBSpriceswillnowbeinfluencedbywhichformularyadrugis

in(Table1).Toaddtothecomplexity,thecriteriadonotapply

tosinglebrandcombinationproducts,astheycouldhave

componentsindifferentformularies.

DrugswhichareinF2arecategorisedaccordingtothesize

ofthediscountstopharmacyasat1october2006.Whenthe

discountwaslessthan25%thedrugisinF2A.Drugswhich

wereheavilydiscountedbymorethan25%areinF2T.The

suppliersofdrugsinthesecategorieswillhavetodiscloseto

theDepartmentofHealthandAgeingtheactualpriceatwhich

theysellabrandtowholesalersorpharmacies.Thisrequirement

appliestonewbrandsofF2Amedicinesfrom1August2007and

tonewbrandsofF2Tmedicinesfrom1January2011.Theaimis

toensurethatthePBSpriceisbasedontheactualsupplierprice

towholesalersorpharmacy.

Apricereductionof12.5%atthetimeofPBSlistingofthe

firstgenericbrandofadrughasbeenrequiredsince2005,

andwillcontinuetoapply.From1August2008,therewillbe

F1containsdrugswithasinglebrand,howeveritdoesnot

containthosesinglebranddrugsthatareinterchangeable

onanindividualpatientbasiswithdrugsthathavemultiple

brandsorsinglebrandcombinationitems.

F2containsdrugswithmultiplebrandsandthosesingle

branddrugsthatareinterchangeableattheindividualpatient

levelwithdrugsthathavemultiplebrands.

Therearemanybalancesinmedicine.DebraKennedy

writesonbalancingtheuseofantipsychoticdrugsduring

pregnancywiththeriskofcongenitalabnormalities,

whileStephenReddeldescribeshowthebenefitsof

immunosuppressionformyastheniagravishavetobe

balancedagainsttheadverseeffects.

PaulKomesaroffdiscussesthedelicatebalancebetween

healthprofessionalsandthepharmaceuticalindustry.

Sometimesthisbalanceisupsetandcanresultinpromotional

activitybreachingtheMedicinesAustraliaCodeofConduct.

Governmentshavetobalancehealthbudgetsandthere

havebeenrecentreformsofthePharmaceuticalBenefits

Scheme.TomFaunceandHansLofgrengivetheirviewof

thechanges.

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 139

furthercompulsorypricereductionsforF2drugs:adropof

2%peryearforthreeyearsfordrugsinF2A,andaone-off

pricereductionof25%fordrugsinF2T(on1August2008).

TherearenomandatorypricecutsfordrugsinF1.Therewillbe

compensationforwholesalersandpharmacistsforthelossof

incomefromstatutoryF2pricereductions.Forexample,from

1August2008pharmacistswillreceive$1.50eachtimethey

dispenseasubstitutablebrandthatcoststhepatientnomore

thantheco-payment.

Manygenericdrugsarealreadypricedbelowthegeneral

patientco-payment,andthepricereductionstodrugsin

F2areexpectedtoresultinmoredrugsfallingunderthe

co-payment.ThePharmacyGuildofAustraliaestimatesthat

thepriceofmorethan400brands,belowthegeneralPBS

co-payment,willfall.4Completepriceandvolumedatawillnot

beavailablefordrugsoncetheyfallbelowthegeneralPBS

co-payment.AlthoughtheDrugUtilisationSub-Committee

ofthePharmaceuticalBenefitsAdvisoryCommittee(PBAC)

receivessomedata,prescriptionsforthesedrugsdonotappear

inofficialstatisticsofPBSexpenditure.

TheMinisterforHealthandAgeinghasstatedthattheroleof

thePBAC,inassessingcost-effectivenessandcostminimisation

andthenadvisingtheMinisteronthelistingofdrugsonthe

PBS,isnotaffectedbythelegislation.5Yettheresponsibilities

ofthePBACwillbeformallyextendedtoincludeadvicetothe

Ministeronexemptionsfrommandatorypricereductions.It

willalsoadviseonwhetherdrugsare'interchangeableonan

individualpatientbasis',astandardmoreuncertainthanthe

previous,moreevidence-based,'equivalence'testsusedto

determineTherapeuticGroupPremiumsforreferencepricing.

Drugsappearing'equivalent'onaverageeffectsmeasured

inclinicaltrials,forexample,maynotbe'interchangeable'

foranindividualpatient.3Forexample,whilecitalopram

andescitalopramwereinthesamereferencepricinggroup,

escitalopramwasinitiallyincludedinF1andcitalopramwas

inF2T.6

Theprincipleofreferencepricing,thatdrugswithidenticalor

similarclinicaloutcomesshouldhavesimilarprices,isintegral

tothearchitectureofthePBSandtherespectithasachieved

internationally.Inourview,theseparationoflisteddrugsinto

twogroups(F1andF2),howeverthisisimplemented,weakens

theroleandfiscalbenefitsofreferencingpricinginthePBS.

AlthoughtherewillbereferencepricingwithinF1,aneffectof

thechangesistoinsulatehighpricedsinglebrand(patented)

F1drugsfrompricecutsandfromthereferencepricingthat

appliedunderpreviousPBSprocesses.3onceanewdrugis

listedonthePBSasF1,itspricewillnotbelinkedtothepriceof

anysimilardruginF2.F1drugsarenotinterchangeableatthe

individualpatientlevelwithdrugsthathavemultiplebrands,

sothemanufacturersmaybeabletoretaintheiroriginalPBS

priceuntilthelistingofabioequivalentbrandsatisfiesthenew

standardsforashifttoF2.ReductionsinF2drugpriceswill

notaffectF1prices,evenwherethetherapeuticeffectofanF2

medicineissimilarthoughnotnecessarily'interchangeableat

theindividualpatientlevel'.

ItisouropinionthatthecreationoftheF1categorywill,over

time,resultinhigherpricesforsomepatenteddrugsthan

wouldhavebeenthecaseunderpreviousPBSarrangements.

Thegovernment'srationaleforthischangeappearstobethat

failuretomakesuchchangescouldresultinlarge'special

patientcontributions'orthewithdrawalofsingle-source

productsfromthePBS.5

Thegovernment,MedicinesAustralia,theConsumers'Health

ForumandseveralprofessionalgroupsviewtheF1–F2changes

asameansofachievinglowerpricesandgreatertransparency

inthegenericsmarket.6However,theexpectationofprice

reductionsflowingtoconsumersispremisedontrustineffective

competitionamongretailpharmacies.Ifdirectbenefitsto

Table 1

Examples of drugs in the new Pharmaceutical benefits Scheme formularies*

F1 F2A F2T

atorvastatin fluvastatin simvastatinbisoprolol carvedilol metoprolol

cefuroxime cephazolin cephalexin

celecoxib ketoprofen naproxen

doxorubicin(pegylatedliposomal) doxorubicin –

levobunolol betaxolol timolol

olanzapine clozapine –

reboxetine – citalopram,fluvoxamine

salmeterol – salbutamol

ticarcillinwithclavulanicacid – amoxycillinwithclavulanicacid

zolmitriptan sumatriptan –– oxazepam diazepam

* asat2007Sep11

140 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

LettersLetters,whichmaynotnecessarilybepublishedinfull,shouldberestrictedtonotmorethan250words.Whenrelevant,commentontheletterissoughtfromtheauthor.Duetoproductionschedules,itisnormallynotpossibletopublishlettersreceivedinresponsetomaterialappearinginaparticularissueearlierthanthesecondorthirdsubsequentissue.

patientsfromlowergenericmedicinespricesorgovernment

supportforanAustraliangenericsindustryhadbeentheprimary

policyobjectives,thenmorebroadlyframedlegislationcould

haveincludedpharmacyrewardsformeetinggenericdispensing

targets,anincentiveperiodofmarketexclusivityforthefirst

genericmarketentrant,andfinancialincentivesforpatientswho

electtobedispensedageneric,orforpatientswhosedoctors

arepreparedtoprescribegenericdrugs.Theroleofthepatented

pharmaceuticalindustryinpromotingandframingthese

changesisalsocontroversial7,particularlyifthenewsystem

allowspricereductionstobedeferredforsomeproducts.

References1. DepartmentofHealthandAgeing.Strengtheningyour

PBS–preparingforthefuture.Canberra;2007.http://www.health.gov.au/internet/wcms/publishing.nsf/Content/A2F23E7630B8F9F3CA257227007F1EC7/$File/strengthening-your-PBS161106.pdf[cited2007nov12]

2. Choice.Prescriptionprices:surveyresultssummary.2006nov.http://www.choice.com.au/viewArticle.aspx?id=105514&catId=100231&tid=100008&p=2&title=Prescription+prices[cited2007nov12]

3. SearlesA,JefferysS,DoranE,HenryDA.Referencepricing,genericdrugsandproposedchangestothePharmaceuticalBenefitsScheme.MedJAust2007;187:236-9.

4. PharmacyGuildofAustralia.SubmissiontoInquiryintonationalHealthAmendment(PharmaceuticalBenefitsScheme)Bill2007.http://www.aph.gov.au/Senate/committee/clac_ctte/nat_hth_pbs_07/submissions/sub07.pdf[cited2007nov12]

5. ParliamentofAustraliaSenateCommunityAffairsCommittee.InquiryintonationalHealthAmendment(PharmaceuticalBenefitsScheme)Bill2007.Submissionsindex.http://www.aph.gov.au/Senate/committee/clac_ctte/nat_hth_pbs_07/submissions/sublist.htm[cited2007nov12]

6. PharmaceuticalBenefitsScheme(PBS)reform.PBSfactsheet.http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbs_reform_02feb07.htm[cited2007nov12]

7. FaunceTA.Referencepricingforpharmaceuticals:istheAustralia-UnitedStatesFreeTradeAgreementaffectingAustralia'sPharmaceuticalBenefitsScheme?.MedJAust2007;187:240-2.

Conflict of interest: none declared

Managing chronic obstructive pulmonary disease

Editor,–Iwonderwhyalpha-1antitrypsindeficiencywasnot

mentionedinthearticleon'Managingchronicobstructive

pulmonarydisease'(AustPrescr2007;30:59–63).Thereis

worldwideevidencethatthisgeneticproblemismuchmore

commonthanitwasthoughtinthepast.InfacttheWorld

Healthorganizationadvisesthateverybodywithchronic

obstructivepulmonarydiseaseshouldbetestedforalpha-1

antitrypsindeficiency,especiallysincethereistreatmentfor

it,thoughnocure.

MichaelAKennedy

Generalpractitioner,retired

Vaucluse,nSW

Professor Michael Abramson, Associate Professor Christine

McDonald and Professor Nicholas Glasgow, authors of the

article, comment:

WethankDrKennedyfordrawingattentiontotherole

ofalpha-1antitrypsindeficiencyinchronicobstructive

pulmonarydisease(CoPD).Thisgeneticdisorderisevidence

fortheelastase–antielastasehypothesisofemphysema.The

prevalenceofseverehomozygous(ZZ)alpha-1antitrypsin

deficiencyhasbeenestimatedataround1/4,727inEuropean

populations.1Although75–85%ofsuchindividualswill

developemphysema,tobaccosmokingisstillthemost

importantriskfactorforCoPDeveninthisgroup.Targeted

screeningsuggests1–4.5%ofpatientswithCoPDhave

underlyingseverealpha-1antitrypsindeficiency.2The

indexofsuspicionshouldbehighinyoungerpatients

withpredominantlybasaldiseaseandafamilyhistory.The

diagnosiscanbemadebymeasuringserumlevelsofalpha-1

trypsin.Iftheyarereduced,genotypingshouldbeperformed.

Whetherpeoplewhoareheterozygous(MZ,MS)arealsoat

anincreasedriskofCoPDremainscontroversial.

Althoughreplacementtherapyisavailable,trialsconducted

todatehavebeenunderpoweredtoconfirmbeneficial

effectsontherateofdeclineinlungfunctionoronsurvival.

oneplacebo-controlledrandomisedtrialsuggestedsome

reductioninthelossoflungtissueasassessedbyCT

scan.3Therapyinvolvesintravenousadministrationof

alpha-1trypsinconcentratepurifiedbyfractionationof

normalhumanplasmaorrecombinantalpha-1trypsin.

Theseproductscanrestorealpha-1trypsinlevelsabovethe

protectivethresholdforsomeweeks.Replacementtherapy

isavailablethroughtheSpecialAccessScheme.Anational

patientsupportgroupcanbecontactedathttp://health.

groups.yahoo.com/group/Alpha1-AnZ.

References

1. BlancoI,deSerresFJ,Fernandez-BustilloE,LaraB,MiravitllesM.EstimatednumbersandprevalenceofPI*SandPI*Zallelesofalpha1-antitrypsindeficiencyinEuropeancountries.EurRespirJ2006;27:77-84.

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 141

2. AmericanThoracicSociety/EuropeanRespiratorySocietystatement:standardsforthediagnosisandmanagementofindividualswithalpha-1antitrypsindeficiency.AmJRespirCritCareMed2003;168:818-900.

3. DirksenA,DijkmanJH,MadsenF,StoelB,HutchisonDC,UlrikCS,etal.Arandomizedclinicaltrialofalpha(1)-antitrypsinaugmentationtherapy.AmJRespirCritCareMed1999;160:1468-72.

A century of concern about complementary medicines

Editor,–ThecommentinAustralian Prescriber(2007;30:91)

drawsunhelpfulandmisleadingparallelsbetween

complementarymedicinestodayand'dangerousanduseless

medicines'available100yearsago.

Theauthorisrighttopointtotheestablishmentofthe

TherapeuticGoodsAdministration(TGA)asanimportant

landmarkfortheregulationofpharmaceuticalsand

complementarymedicines.TheComplementaryHealthcare

Council(CHC)fullysupportsaregulatoryprocessthat

safeguardsconsumerinterests.However,tosuggest

thatcomplementarymedicinesastherapeuticgoodsare

somehowcompromisedbyfalseormisleadingadvertisingor

thatbarriersexisttounderstandingthembecausesponsors

hidebehind'commercial-in-confidence'isinaccurate.

Alladvertisementsfortherapeuticgoodsaresubjectto

theTherapeuticGoods,TradePracticesandotherrelevant

laws.TheTherapeuticGoodsAdvertisingCode,which

appliestoadvertisementsdirectedtoconsumersandwhere

sanctionsapplyforbreaches,requiresmaterialtobetruthful,

balanced,notcontainmisleadingorexaggeratedclaims,and

alldescriptions,claimsandcomparisonsmustbeabletobe

substantiated.

Withregardto'commercial-in-confidence',itishardtosee

howconcernsregardingtransparencywouldnotequally

applytopharmaceuticalcompanies.Companiesresponsible

formarketingproductsareobligedtomakeavailableall

evidenceregardingclaimsinrelationtotheirproducts,

shouldtheybeaskedtodosobytheTGA.

WhatdoesconcerntheCHC,istheoutdatedattitudes

demonstratedtowardscomplementarymedicines,despite

repeatedandcompellingevidencedemonstratingtheir

healthbenefits.Let'simagineforonemomenttheimplication

forpregnantwomenglobally,iffolatesupplementationin

preventingneuraltubedefectshadnotbecomeaccepted

mainstreampractice.

TonyLewis

ExecutiveDirector

ComplementaryHealthcareCouncil

Canberra

Dr JS Dowden, the author of the comment, responds:

ThereisLevel1evidencetosupporttheuseoffolate

supplementsbywomenplanningpregnancy.Itisdoubtful

thatsuchstrongevidenceexistsformanycomplementary

products.Giventheplethoraofcomplementarymedicines

itisunlikelythattheTGAhastheresourcestoassessthe

evidenceformanyoftheseproducts.Evidenceofaproduct's

safetyandefficacyshouldnotbe'commercial-in-confidence'

irrespectiveofwhetheritisaprescriptionoranon-

prescriptiondrug.

Despitethesomewhatconfusingregulatorysystem,

thereareplentyofcomplaintsabouttheadvertisingof

complementarymedicines.1Theusualsanctionforan

unacceptableadvertisementseemstobearequestfor

theadvertisementtobewithdrawn,butitisunclearhow

effectivelythisisenforced.2

octaviusBealewasconcernedabouttheoutrageousclaims

beingmadebymedicinesmanufacturersintheearly

20thcentury.3Thenumberofjustifiedcomplaintsin2007

suggeststhatthereisstillaproblem.1

References

1. http://www.tgacrp.com.au/index.cfm?pageID=13[cited2007oct30]

2. http://www.medreach.com.au/Downloads/SPH_Complementary_Medicines.pdf[cited2007oct30]

3. ReportbyRoyalCommissiononSecretDrugs,CuresandFoods.BealeoC.Parliament,Australia.Sydney:CommonwealthofAustralia;1907.

Magnesium

Editor,–InthearticleonmagnesiumbyDrWuandDrCarter

(AustPrescr2007;30:102–5)thereislittleattempttoaddress

theissueofcrampsandmagnesiumingestionbythepublic.

Myclinicalexperiencehasbeenthateveryagedpatient

whohasanyproblemwithcramping,haseithertried,oris

on,oralmagnesiumusuallyfromthesupermarketorhealth

store.Thisisoftenmagnesiumphosphate.

Couldtheauthorscommentontheissueofcrampingand

adultsovertheageoffiftyyears?Isthereanyevidencethat

lackofmagnesiumcausesthis,orthatoralmagnesiumisof

anybenefit?

ChrisCommens

Dermatologist

PennantHills,nSW

Dr J Wu and Dr A Carter, authors of the article, comment:

InresponsetoProfessorCommens,aliteraturesearch

performedinconsultationwithourpharmacologyunit

failedtoraiseanyconclusiveevidencethatmagnesium

phosphateisusefulinpreventingcrampsintheelderly.This

isnottosaythatbiochemicallyprovenhypomagnesaemia

wouldnotrespondtosupplementation,inthesamewayas

hypocalcaemiaorhypokalaemiawouldrequirecalciumor

potassiumsupplementationrespectively.

142 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

Top 10 drugsThesetablesshowthetop10subsidiseddrugsin2006–07.Thetablesdonotincludeprivateprescriptions.

Table 1

Top 10 drugs supplied by DDD*/1000 pop/day †

Drug PbS/RPbS ‡

1. atorvastatin 131.7992. simvastatin 58.0723. ramipril 30.4514. perindopril 21.6815. aspirin 18.016. omeprazole 17.9967. frusemide 17.9848. irbesartan 17.289. salbutamol 17.11610. esomeprazole 16.802

Table 2

Top 10 drugs by prescription counts †

Drug PbS/RPbS ‡

1. atorvastatin 100004952. simvastatin 62312123. esomeprazole 44285304. omeprazole 38823595. paracetamol 37541406. perindopril 36335367. atenolol 32171518. irbesartan 29893599. pantoprazole 292272410.metforminhydrochloride 2822776

Table 3

Top 10 drugs by cost to Government †

Drug Cost to Government DDD/1000/day Prescriptions ($A) PbS/RPbS ‡ PbS/RPbS ‡

1. atorvastatin 562234406 131.799 100004952. simvastatin 309227367 58.072 62312123. clopidogrel 179983732 9.219 24043614. esomeprazole 161102420 16.802 44285305. olanzapine 157471533 3.073 7754756. salmeterolandfluticasone 157239113 –§ 27898147. omeprazole 114030881 17.996 38823598. pravastatin 93389809 13.537 18708799. venlafaxine 93329210 11.987 231853110. tiotropiumbromide 91223529 5.289 1303682

* Thedefineddailydose(DDD)/thousandpopulation/dayisamoreusefulmeasureofdrugutilisationthanprescriptioncounts.Itshowshowmanypeople,ineverythousandAustralians,aretakingthestandarddoseofadrugeveryday.

† Basedondateofsupply‡ PBSPharmaceuticalBenefitsScheme,RPBSRepatriationPharmaceuticalBenefitsScheme§ CombinationdrugsdonothaveaDDDallocated

Source:DrugUtilisationSub-Committee(DUSC)DrugUtilisationDatabase,asat11october2007.©CommonwealthofAustralia.

NPS RADAR December 2007

Strontiumranelate:ThePBSlistingfortheosteoporosisdrug

strontiumranelatehasbeenextendedtoallowtreatmentof

postmenopausalwomenwithoutanexistingfractureanda

bonemineraldensityT-score≤–3.0(primaryprevention).The

latestissueofNPS RADAR describestheplaceintherapyof

strontiumrelativetootheranti-resorptiveagents.

Italsocontainsinformationon:

n thelistingoftheanticonvulsantdrugtopiramateasan

alternativetreatmentformigraineprevention,foradults

unabletotoleratebetablockersorpizotifen

n updatedsafetyinformationfortheglitazones–rosiglitazone

andpioglitazone.

Seethecompletereviewsatwww.npsradar.org.au

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 143

Drugs for the doctor's bagAndrew Baird, General Practitioner, Brighton, Victoria

Summary

The doctor's bag should contain drugs for medical emergencies that may occur in the community. Most of these drugs are provided under the Pharmaceutical benefits Scheme and can be ordered free of charge through a pharmacist. General practice accreditation now requires that clinics have appropriate emergency drugs as well as oxygen and a bag-valve-mask system. Practices should also have an up-to-date logbook detailing the emergency drug stocks and a system for checking that the drugs have not expired.

Keywords:medicalemergencies,PharmaceuticalBenefits

Scheme.

(Aust Prescr 2007;30:143–6)

introductionTraditionallythedoctor'sbagcontainsdrugsandequipment

formanagingmedicalemergenciesthatpresentintheclinicor

inthecommunity.1,2,3Thefrequencyandtypeofemergencies

thatoccurdependonthelocationandnatureofthepractice.

WiththeincreasingavailabilityofskilledMobileIntensiveCare

Ambulance(MICA)paramedicsas'firstresponders',manygeneralpractitionershavebecomelessinvolvedinmanaging

emergencies.However,inruralandremoteareasthedoctorwill

oftenbethe'firstresponder'andmaybeworkingwithvolunteer

ambulancecrews.

what to carryDoctorsshouldconsiderthemedicalemergenciesthatthey

mayencounterintheirpracticeandselectappropriatedrugsfor

theirdoctor'sbag(Table1).Manyofthesedrugsareprovided

underthePharmaceuticalBenefitsScheme(PBS)asEmergency

drug(Doctor'sbag)supplies.4Mostofthemareinjectable.

However,therearesomenon-injectabledrugswhichareuseful

inemergencies,suchassolubleaspirin,glyceryltrinitrate

(sublingualspray)andsalbutamolaerosol.

Doctorscansubmitamonthlyorderform*toapharmacistfor

thesupplyofPBSdoctor'sbagemergencydrugsatnocost.

SomePBSdrugsaresuppliedaspairedalternatives.These

includehydrocortisoneordexamethasoneandmetoclopramide

orprochlorperazine.Agrouppracticecanhaveallofthesedrugs

availableifdoctorsagreetoorderoneorotheritemineachpair.

Adrugcanonlyberequestedifthedoctorholdslessthanthe

maximumquantityprovidedunderthePBS,ortoreplace

date-expireddrugs.

Somedrugswhichareusefulforemergenciesarenotprovided

underthePBS(Table1).Doctorsmayobtaintheseasprivate

itemsbysubmittingawrittenordertoapharmacist.These

drugsinclude:

n oraldrugssuchasaspirin,analgesics,diazepam,antibiotics,

prednisolone

n non-steroidalanti-inflammatorydrugs(nSAIDs)forrectalor

intramuscularuse

n glucose50%

n ceftriaxone

n midazolam

n ergometrine.

Itisalsousefultocarryatleastone1Lbagofnormalsaline,

andasupplyofnormalsalineandwaterforinjections.

Current practice guidelinesEmergencydrugsavailablethroughthePBSsometimesdiffer

fromthoserecommendedbyAustraliantreatmentguidelines.

Forexample,theuseofparenteralchlorpromazineisnot

recommendedbytheTherapeuticGuidelinesbecauseitcan

causeserioushypotension.Instead,oralpreparationsof

risperidone,olanzapineorhaloperidolarerecommendedfor

behaviouralemergenciesiforaldiazepamisnoteffective.5

onlyinjectableformsofdiazepamandhaloperidolare

providedasemergencydrugsbythePBS.

LignocaineisaPBSdoctor'sbagitem.However,other

treatmentsforsustainedventriculartachycardiamaybe

preferred.5

Precautions with emergency drugsWithsedatingdrugs,thereisariskofdeathfromrespiratory

depression,especiallywhengivenintravenously.Itis

thereforeimportanttokeepthepatientunderobservationafter

administrationofthesedrugs.

Pethidineisnolongersuppliedasadoctor'sbagitem.6Instead,

aninjectableformoftramadolisnowavailablethroughthePBS.

Tramadolshouldnotbeusedinpatientstakingaserotonergic

antidepressantbecauseoftheriskofserotoninsyndrome.

Doctorsshouldbeawarethatketorolacshouldnotbegivento

patientswithrenalimpairment.* orderformsareobtainablefromMedicareAustralia,

phone132290.

144 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

Table 1

useful drugs for the doctor's bag

Drug (form) indications Contraindications Cautions

Adrenaline(1mgin1mLinjection)

Cardiacarrest,anaphylaxis7 noneincardiacarrestoranaphylaxis

Maycausearrhythmiaandmyocardialorcerebrovascularischaemia

†Aspirin,soluble,300mgtablet

Acutecoronarysyndrome,migraine

Pepticulcer,bleedingdisorders none

Atropinesulfate(600microgramin1mLinjection)

Bradycardia,asystole noneincardiacarrestorhypotensivebradycardia

Maycausetachycardia,confusionandnausea

Benztropinemesylate(2mgin2mLinjection)

Acutedystonicreactions Children<3years Maycausetachycardiaandconfusion

Benzylpenicillin(600mgor3gofpowder)

Severeinfections(meningococcaemia,pneumonia,septicaemia)

Allergy none

†Ceftriaxone(2gpowder)

Severeinfections(meningococcaemia,pneumonia,septicaemia)

Allergy none

Dexamethasonesodiumphosphate(4mgin1mLinjection)

Acuteallergicreactions(anaphylaxis,severeasthma),severecroup,acuteAddisoniancrisis.Palliativecareemergencies8

noneinemergency none

Diazepam(10mgin2mLinjection)

Acuteanxiety,convulsions(canbegivenrectally)

Cardiorespiratoryfailure,

CnSdepression

Maycausedrowsiness,confusionandrespiratorydepression

Dihydroergotaminemesylate(1mgin1mLinjection)

Migraine Hemiplegicmigraine,useofsumatriptan

Vasospasmsyndromescanoccurbutarerare

Diphtheriaandtetanusvaccine(0.5mLinjection)

Tetanusanddiphtheriaprophylaxisfollowinginjury

Children<8years Maycausepainandswellinglocallyandfeverandmalaise

†Ergometrinemaleate(500microgramin1mL)

Postpartumhaemorrhageandincompleteabortion

Threatenedabortion,severehypertension

Maycausehypertension,headacheandnausea

Frusemide(20mgin2mLinjection)

Acutepulmonaryoedema Sulfonamideallergy none

Glucagonhydrochloride(1mgin1mLinjection)

Hypoglycaemia none none

†Glucose50%(500mg/mLin50mL)

Hypoglycaemia Diabeticcoma Maycausephlebitis

Glyceryltrinitrate(400microgramdoseperspray)

Acutecoronarysyndrome,angina,acutepulmonaryoedema

Cardiogenicshock(SBP<90mmHg)

Maycauseheadacheandhypotension

Haloperidol(5mgin1mLinjection)

Acutepsychosis,acutemania,nauseaandvomiting

CardiovascularcollapseandCnSdepression

Maycauseextrapyramidalsymptoms,confusionandhypotension

Hydrocortisonesodiumsuccinate(100mgor250mgin2mLinjection)

Anaphylaxis,severeasthma noneinemergency none

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 145

†Ketorolac(10mgin1mLinjection)

Pain Renalimpairment,anticoagulation,asthma,treatmentwithprobenecid

Maycausenausea

Metoclopramidehydrochloride(10mgin2mLinjection)

nauseaandvomiting,migraine Acutecompletebowelobstruction

Extrapyramidalsymptomswithincreasedriskofdystonicreactionsinchildren

†Midazolam(5mgin1mLor15mgin3mLinjection)

Convulsions,severeagitation CardiorespiratoryfailureandCnSdepression

Maycausedrowsiness,confusionandrespiratorydepression

Morphinesulphate(15mgor30mgin1mLinjection)

Severepain,acutecoronarysyndrome,acutepulmonaryoedema

RespiratoryorCnSdepression.Avoidusingininfants.

Maycausesedation,nauseaandvomiting

naloxonehydrochloride(2mgin5mL)

opioid-inducedrespiratorydepression

none Peoplewithopioiddependencemayexperienceacutewithdrawalsyndrome

Procainepenicillin(1.5gforinjection)

Severeinfections(meningococcaemia,pneumonia,septicaemia)

Allergy none

Prochlorperazine(12.5mgin1mL)

nauseaandvomiting,vertigo CirculatorycollapseandCnSdepression

Maycausedrowsinessandextrapyramidalsymptoms

Promethazinehydrochloride(50mgin2mLinjection)

nauseaandvomiting,allergicreactions

Children<2years(exceptonadvice)

Maycausedrowsiness

Salbutamolsulfate(inhaler100microgram/doseornebulisersolution2.5mgor5mgin2.5mL)

Asthma,bronchospasm none Maycausetachycardiaortremor

Tramadolhydrochloride(100mgin2mLinjection)

Pain Children,treatmentwithserotonergicantidepressantsorMAoIs,respiratoryorCnSdepression

Maycausenausea,vomitinganddizziness

Verapamilhydrochloride(5mgin2mLinjection)

Supraventriculartachycardia Cardiogenicshock,heartblock,hypotension,useofbetablockersandsomeSSRIs

Maycausenausea,heartblock,bradycardiaandhypotension

† notsuppliedunderPBSdoctor'sbagemergencydrugsCnS centralnervoussystemSBP systolicbloodpressureMAoI monoamineoxidaseinhibitorSSRI selectiveserotoninreuptakeinhibitor

oxygenoxygencylinderscanberentedandrefilledfromamedicalgas

supplier(forexampleBoC(BritishoxygenCorporation)).A490L

(sizeC)willlastfor55minutesat8L/min.Usehigh-flowoxygen

withcautioninpatientsathighriskofcarbondioxideretention.

Storage of drugsDrugsmustbestoredinalockedbagoralockedcupboardat

below25°C.Doctor'sbagsshouldnotbeleftincarswhere

thetemperaturewilleasilyexceed25°Conevenamildday.

Diphtheriaandtetanusvaccineisstoredinarefrigerator.

Aregisterisrequiredtologdrugsreceivedanddrugsused

(includingtherecipient'sname).Schedule8drugs(opioids)

mustbestoredinalocked,fixed,steelsafe,althoughampoules

maybeputinalockedbagforuseawayfromtheclinic.A

separatebook(availablefromtheRoyalAustralianCollegeof

GeneralPractitioners)isrequiredtologSchedule8drugsthat

arereceivedandused.

Drug (form) indications Contraindications Cautions

146 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

General practice accreditationTomeetaccreditationstandards,generalpracticesmusthave

oxygen,abag-valve-masksystem,andappropriateemergency

drugs.Allgeneralpractitionersmusthaveaccesstoadoctor's

bag(whichmaybesharedbetweentwoormoregeneral

practitioners).Thereshouldbeasystemforcheckingemergency

drugstocksandexpirydates–forexample,amonthlyinventory

byapracticenurse.Doctor'sbagsshouldhaveasharps

container,disposablegloves,anddressingpacks.Safety

intravenouscannulasandneedlelesssystemsreducetherisk

ofneedlestickinjury.3

ConclusionAppropriatedrugsinthedoctor'sbagareanessentialpartof

generalpractice.Thecontentsofthebagwillbetailoredtosuit

theneedsofeachpractice.

References1. MurtaghJ.Drugsforthedoctor'sbag.AustPrescr

1996;19:89-92.2. MurtaghJ.Thedoctor'sbag–whatdoyoureallyneed?

AustFamPhysician2000;29:2509.3. Hiramanekn,o'SheaC,LeeC,SpeechlyC,CavanaghK.

What'sinthedoctor'sbag?AustFamPhysician2004;33:714-20.

4. PharmaceuticalBenefitsScheme:Doctor'sbagitemlist.http://www.pbs.gov.au/html/healthpro/browseby/doctorsbag[cited2007nov12]

Dental notes

Prepared by Dr M McCullough of the Australian Dental Association

Drugs for the doctor's bag

Dentistsdonotneedtostockasmanyemergencydrugsas

generalpractitioners,howeverwearerequiredtohavefully

equippedandwellmaintainedemergencyequipmentinour

surgery.

AsstatedintherecentlypublishedTherapeuticGuidelines:

oralandDental1,theminimumrequirementsforemergency

situationsinthedentalsurgeryareoxygen,adisposableairway,

andadrenaline.Fordentalpracticesperformingmoreextensive

procedures,orwithanincreasedproportionofmedically

compromisedpatients,thenmoreequipmentandmedications

arerequired.

Medicalemergenciesindentalsurgeriesareuncommonso

thereisariskthatmedicationswillexpirebeforetheyare

needed.Itisincumbentondentiststoensurethatthedrugsin

theiremergencyequipmentarenotoutofdate.Ideally,there

shouldbeasystemforcheckingemergencydrugstocksand

expirydates,perhapsbyamonthlyinventory.Manydental

practicesprobablyalreadyhavesuchaninventoryanditcanbe

easilyforeseenthatsuchdocumentationmaywellbecomepart

ofanypotentialpracticeaudit.

EmergencydrugsarenotavailableunderthePharmaceutical

BenefitsSchemefordentistsandmustbepurchasedatfullcost.

Thisanomalyshouldberedressed.

Reference1. TherapeuticGuidelines:oralandDental.Version1.

Melbourne:TherapeuticGuidelinesLimited;2007.

5. eTGcomplete.TherapeuticGuidelines.2006oct.http://www.tg.com.au[cited2007nov12]

6. MolloyA.Doespethidinestillhaveaplaceintherapy?AustPrescr2002;25:12-13.

7. Emergencymanagementofanaphylaxisinthecommunity.Wallchart[insert].AustPrescr2007;30(5).

8. SeidelR,SandersonC,MitchellG,CurrowDC.Untilthechemistopens–palliationfromthedoctor'sbag.AustFamPhysician2006;35:225-31.

Further readingAustralianResuscitationCouncilguidelines.http://www.resus.org.au[cited2007nov12]

Adultcardiorespiratoryarrestflowchart.http://www.resus.org.au/public/arc_adult_cardiorespiratory_arrest.pdf[cited2007nov12]

Paediatriccardiorespiratoryarrestflowchart.http://www.resus.org.au/public/arc_paediatric_cardiorespiratory_arrest.pdf[cited2007nov12]

nationalAsthmaCouncil.Emergencymanagementofasthma.http://www.nationalasthma.org.au/html/emergency/print/EMAC.pdf[cited2007nov12]

nationalHeartFoundation.Emergencydepartment/CCUguidelinesforthemanagementofacutecoronarysyndrome.ACStherapyalgorithm.http://www.heartfoundation.org.au/document/nHF/acs_chart0506.pdf[cited2007nov12]

Conflict of interest: none declared

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 147

Evaluation of adrenocortical function in adultsJui Ho, Endocrinologist, and David J Torpy, Associate Professor, Discipline of Medicine, University of Adelaide, and Endocrine and Metabolic Unit, Royal Adelaide Hospital, and Hanson Institute, Adelaide

Abnormallaboratoryresults

Summary

Cushing's syndrome is caused by increased

concentrations of cortisol. Most cases can be

detected by measuring the free cortisol in a urine

sample collected over 24 hours. in Cushing's

syndrome the increased secretion of cortisol is

not reduced during a dexamethasone suppression

test. Addison's disease is caused by a decreased

secretion of cortisol that does not respond to

an injection of synthetic adrenocorticotrophic

hormone. Concentrations of adrenocorticotrophic

hormone are raised in primary, and low or normal

in secondary adrenal insufficiency. Some patients

with hypertension have primary aldosteronism.

They have a high ratio of aldosterone to plasma

renin activity. when investigating adrenal function

it is important to consider the patient's diet and

drugs as well as the timing of the sample.

Keywords:Addison'sdisease,aldosterone,Conn'ssyndrome,

cortisol,Cushing'ssyndrome.

(Aust Prescr 2007;30:147–9)

introduction

Theadrenalcortexconsistsofthreefunctionallyseparate

layers.Theouterzonaglomerulosaproducesaldosterone

underthestimulatorycontroloftherenin-angiotensinsystem

andpotassium.Aldosteroneincreasessodiumreabsorption

andpotassiumexcretioninthekidneyandgut.Thezona

fasciculataproducescortisolunderthecontrolofpituitary

adrenocorticotrophichormone(ACTH).ACTHisprincipally

regulatedbyhypothalamiccorticotrophin-releasinghormone.

ThesecretionofACTHrespondstoadiurnalrhythm,stressand

negativefeedbackfromcirculatingcortisol.Cortisolregulates

metabolism,andduringstressitrestrainsandredirectsthe

immunesystemandaccentuatescardiovascularresponses.

Theinnerzonareticularisproducestheadrenalandrogens

dehydroepiandrosteroneandandrostenedione.

Clinicalevaluationdetermineswhichtestsofadrenalfunction

areneeded.Theprinciplesoftestinginclude:

n usingbasalhormoneconcentrationsforscreening

n usingsuppressionorstimulationteststodefinitively

diagnosehormoneexcessordeficiency

n measuringtrophichormonestodiagnosethesite

ofendocrinelesions(forexample,measuringACTH

todistinguishanadrenalfromapituitarylesionin

hypocortisolism).

Testing for hypercortisolism (Cushing's syndrome)MildCushing'ssyndromeisnotoriouslydifficulttodiagnose,

butearlydiagnosisavoidsdisabilityandreducesmortality.

CortisolconcentrationsincreaseinCushing'ssyndrome,but

therearetwomajorconfounders.oneisthatsomepatients

haveincreasedcortisolproductionratesthatremainwithinthe

statisticallynormalrange.Furthermore,thisoverproduction

maybeintermittentorcyclic.Secondly,someindividualsmay

havetransienthypercortisolismandfeaturesconsistentwith

earlyCushing'ssyndrome,butwithouttheprogressivecatabolic

effects.Theseindividualshave'pseudo-Cushing's'.Insome

casesthisisassociatedwithalcoholabuseordepression.no

singletestisinfallibleinCushing'ssyndromeandvaluesclose

tothelimitsofnormalmustberegardedwithsuspicion.1

Screening tests for Cushing's syndromeMostcasescanbereadilydiagnosedbyanelevationofthefree

cortisolina24-hourcollectionofurine,howeverinupto15%

ofnewcasestheresultmaybenormal.Thedexamethasone

suppressiontestalsohasasubstantialfalsepositiveandfalse

negativerate.Thediagnosiscanbemadewithplasmacortisol,

butthebloodsamplehastobetakenatmidnightandthis

isoftenimpractical.Amidnightvaluelessthan120nmol/L

virtuallyexcludesCushing'ssyndrome.

Urinary free cortisolover24hoursthefreecortisolprovidesanintegrated

assessmentofcortisolsecretion.Thisavoidsthepitfallsof

bloodtestsincludingcircadianrhythm,pulsatilecortisolrelease

andalteredlevelsofcorticosteroid-bindingglobulin.However,

148 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

urinevolumesabovefourlitresperdaymayresultinfalse

positivetests.

Cortisolexcretionratesvarydiurnallybuturinecreatinine

excretiondoesnot.Hence,itisnotpossibletocorrectan

incompleteorover-collectionwiththe24-hoururinecreatinine.

Urinarycreatinineisusefulindeterminingiftheurinecollection

wasadequate,forexamplealow24-hoururinecreatininein

alargepersonmaysuggestunder-collection.Inaddition,in

sequentialmeasurementsthe24-hoururinecreatinineshould

notvarybymorethan10%.

Falsepositiveresultscanoccurinpatientswithhighurine

volumes,chronicalcoholism,depression,idiopathicpseudo-

Cushing's,orseriousillness.Falsenegativesmayoccurin

patientswithearlyormildCushing'ssyndrome,orinthosewith

cyclichypercortisolismwhichoccursin10%ormoreofcases

dependingonhowcyclicisdefined.

Midnight plasma cortisolCortisolpeaksaroundthetimeofwaking,decreasesrapidly

throughthemorningandreachesanadiraroundmidnight.Most

patientswithCushing'ssyndromehaveearlymorningplasma

cortisolconcentrationswithinorslightlyabovethenormalrange.

Incontrast,midnightplasmacortisolconcentrationsarealmost

alwayshigh(greaterthan207nmol/L).

Midnight salivary cortisolSalivarycortisolconcentrationsreflectplasmafreecortisol,but

appropriateassay-specificnormativevaluesmustbeusedfor

itsinterpretation.Internationally,cut-offshaverangedwidely.

Wehavefoundacut-offof13nmol/Ltoreliablydistinguish

Cushing'sfromnon-Cushing'spatients.

Low-dose dexamethasone suppression testingAlowdoseofdexamethasoneshouldsuppressplasmacortisol.

ThisiscommonlyusedasascreeningtestforCushing's

syndrome.Dexamethasone,1mgorally,isgivenat11pmand

plasmacortisolismeasuredat8–9amthenextdaytoseeifit

hasbeensuppressed.Thedexamethasonesuppressiontesthas

beenvariouslyvalidatedinthepast,oftenwithinappropriate

controls,suchasnormalvolunteers.Lowcut-offvalues

(50nmol/Lorless)tendtoover-diagnose,whilehighcut-off

values(140nmol/Lorabove)tendtomisscasesofCushing's

syndrome.Falsepositiveresultscanoccurinacuteillness,

depression,anxiety,alcoholism,highoestrogenstatesand

withdrugsthatacceleratedexamethasonemetabolism.Ifalow

dosedoesnotsuppresscortisol,ahigh-dosedexamethasone

suppressiontestisindicated.

Testing for primary hypoadrenalism (Addison's disease) and ACTH deficiencyHypoadrenalismmaybecausedbyabnormalitiesintheadrenal

glandoralackofACTH.Adrenalsuppressionisalsoanadverse

effectofcorticosteroids.

Althoughfatigueisakeysymptomofhypoadrenalism,most

fatiguedpeoplehavenormaladrenalfunction.Thereisnosingle

cheapandconvenienttestforevaluatinghypoadrenalism.2Testing

includesanACTHstimulationtest,andmeasurementsofsodium,

potassium,ACTH,plasmacortisol,aldosteroneandreninactivity.

Plasma cortisolAnearlymorningplasmacortisol,measuredwithinone

hourofwaking,below200nmol/Lstronglysuggestsadrenal

insufficiency.Conversely,aplasmacortisolgreaterthan

500nmol/Lexcludesthediagnosisandobviatestheneedforan

ACTHstimulationtest.Intermediatecortisolconcentrationsmay

requireinvestigationwithanACTHstimulationtest.

ACTH stimulation testingInmostcasesofsuspectedhypoadrenalism,astimulationtest

isneededtodiagnosecortisoldeficiency.Anormalresponseto

intravenousACTH(250microgram)isacortisolpeakvalueat

either30or60minutesofgreaterthan500nmol/L.Thepreviously

recommendedadditionalcriterionofacortisolincrementgreater

than200nmol/Lrarelycontributestothediagnosis.

Therearecasesofmissedadrenalinsufficiencyafteranormal

ACTHtest.Thereproducibilityoftestingisimperfect.Thetest

hasnotbeenvalidatedagainstclinicalendpoints,buthasbeen

validatedagainstthenowrarelyusedinsulinhypoglycaemiatest.

Plasma ACTHMeasurementofplasmaACTHhelpslocalisethecauseof

adrenalinsufficiency–adrenal(primaryorAddison's)versus

pituitary(secondary)orhypothalamic(tertiary).Inprimary

adrenalinsufficiency,plasmaACTHisgreatlyelevatedduetoa

lackofthenegativefeedbackofcortisolonthehypothalamic-

pituitaryaxis.Insecondaryortertiaryadrenalinsufficiency,

ACTHisloworinappropriatelynormal.

Corticotrophin-releasing hormone testTheuseofcorticotrophin-releasinghormonetotestACTHand

cortisolreservedirectlyassessespituitaryandadrenalfunction.

otherthanminorflushing,corticotrophin-releasinghormone

(1microgram/kgintravenously)rarelyproducesadverseeffects.

Thetestisexpensiveandcorticotrophin-releasinghormoneis

notwidelyavailable.

Testing for primary aldosteronismConn'ssyndromeishypertensionandhypokalaemiaduetoan

aldosterone-secretingadrenaltumour,howevermanycasesare

normokalaemic.Screeningforprimaryaldosteronismmaybe

indicatedinpatientswithhypertensionwhohavespontaneous

orthiazide-inducedhypokalaemia.3

Plasma aldosterone concentration:plasma renin activity ratioAmid-morningbloodsampleistakenfromaseatedpatient.

Inprimaryaldosteronism,theplasmareninactivityisreduced

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 149

andtheplasmaaldosteroneconcentrationsarehigh,resulting

inaplasmaaldosteroneconcentration(pmol/L):plasmarenin

activity(ng/mL/hr)ratioofgreaterthan700.Afalsepositive

mayoccurwithlowaldosteroneconcentrationsiftheplasma

reninactivityisverylow,forexampleinpatientstakingahigh

saltdiet.Hence,anelevatedratiomaynotsuggestprimary

aldosteronismiftheplasmaaldosteroneconcentrationisless

than270nmol/L.

Serumpotassiumshouldbemeasuredsimultaneouslyas

alowserumpotassiumwillreducetheplasmaaldosterone

concentrationandindicatearequirementtoreplacepotassium

beforetestingagain.Antihypertensivedrugs,exceptfor

hydralazine,prazosinandverapamil,canalsointerferewith

theplasmaaldosteroneconcentration:plasmareninactivity

ratio.Diureticsandaldosteronereceptorblockerssuchas

spironolactoneneedtobestoppedforsixweeksbeforetesting.

Betablockerssuppresstheplasmareninactivitybutthey

canbestoppedfor24–48hoursbeforetesting.Theeffectsof

angiotensinconvertingenzyme(ACE)inhibitorsandangiotensin

receptorantagonistsaregenerallyminor,butinapatienttreated

withthesedrugsadetectableplasmareninactivitylevelora

lowplasmaaldosteroneconcentration:plasmareninactivity

ratiodoesnotexcludethediagnosisofprimaryaldosteronism.

Dihydropyridinecalciumantagonistssuchasnifedipineand

amlodipinecanreducetheplasmaaldosteroneconcentration

inpatientswithanaldosteronesecretingadenoma.Renal

impairmentmayelevatetheratioasincreasedpotassium

elevatesaldosteronesecretionwhilesaltandwaterretention

suppressestheplasmareninactivity.

Confirming primary hyperaldosteronismConfirmatorytestingaimstodemonstratealdosterone

secretoryautonomy,usingmeasurementsofplasmaorurine

aldosteroneundersaltloadingconditions,withorwithout

fludrocortisone.Thefinalstepistodetermineifoneorboth

adrenalsarethesourceofaldosterone,generallyrequiring

adrenalveinsampling.

Adrenal incidentalomaAnunanticipatedadrenalmass(incidentaloma)isfoundin

approximately4%ofupperabdominalcomputedCTscans.

Clinical,imagingandbiochemicalevaluationisnecessaryto

excludemalignancyandhormoneexcess.4Theriskof

adrenocorticalcancerisverylow,butadrenalmetastasesare

commonandneedtobeconsideredinpatientswithahistory

ofcancer.

ConclusionDisordersofadrenocorticalfunctionareuncommonandthe

symptomsoftennon-specific.Applicationofasmallnumberof

biochemicalscreeningtestscanseparatethosepatientswhodo

nothaveadisorderofadrenalfunctionfromthosewhorequire

specialisedassessmentandmorecomplextesting.

References1. newell-PriceJ,BertagnaX,GrossmanAB,niemanLK.

Cushing'ssyndrome.Lancet2006;367:1605-17.2. niemanLK.Dynamicevaluationofadrenalhypofunction.

JEndocrinolInvest2003;26(7Suppl):74-82.3. MulateroP,DluhyRG,GiacchettiG,BoscaroM,VeglioF,

StewartPM.Diagnosisofprimaryaldosteronism:fromscreeningtosubtypedifferentiation.TrendsEndocrinolMetab2005;16:114-19.

4. nationalInstitutesofHealth.nIHstate-of-the-sciencestatementonmanagementoftheclinicallyinapparentadrenalmass('incidentaloma').nIHConsensStateSciStatements2002;19:1-25.

Conflict of interest: none declared

Self-test questionsThe following statements are either true or false

(answers on page 167)

1. Mostpatientswithprimaryhyperaldosteronismhave

hyperkalaemia.

2. Anormal24-hoururinefreecortisolexcludesCushing's

syndrome.

Therapeutic Advice and information Service (TAiS)A telephone service for health professionals Telephone 1300 138 677 (local call charge)

ThenationalPrescribingServiceTherapeuticAdviceand

InformationService(TAIS)isanationaltelephoneservice

forgeneralpractitioners,communitypharmacistsandother

healthprofessionals.Forthecostofalocalcall,TAIS

providesindependentdrugandtherapeuticsinformation

ontopicssuchasnewdrugs,useofdrugsforunlicensed

indications,interactionsbetweendrugs,foodsor

complemetarytherapies,adverseeffects,andthesafetyof

drugsinpregnancyandlactation.

Contact: officehours MondaytoFriday,exceptnational

publicholidays

Telephone: 1300138677(localcallcharge)Fax: (03)94594546Email: tais@nps.org.auMail: AustinHealthDrugInformation PharmacyDepartment AustinHospital 145StudleyRoad

HEIDELBERGVIC3084

Fornon-urgentenquiriesyoucanalsousetheTAISonlineenquiryformonthenPSwebsite.

150 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

Relationships between health professionals and industry: maintaining a delicate balancePaul A Komesaroff, Professor of Medicine, Director, Centre for the Study of Ethics in Medicine and Society, Monash University Department of Medicine, Alfred Hospital, Melbourne, and Ethics Convener, Royal Australasian College of Physicians

Summary

The power and influence of the pharmaceutical industry has raised concerns among health professionals and the wider community and led to calls for increased regulation. overwhelming evidence that advertising, contact with company representatives, gift giving, sponsorship of meetings and other forms of promotion influence prescribing behaviour, has drawn particular attention to drug promotion. in answer to these concerns a range of responses has developed, including rules set by government, processes for the review and management of research, industry codes of conduct, community responses, and guidelines generated by practitioner associations. The various forms of regulation taken together strike a delicate balance that aims to protect the interests of the community and individual patients, foster research and the development of new products, maintain public confidence in pharmaceuticals and medicine, and facilitate ethical decision making among the various participants. Although guidelines for health professionals provide some advice, they cannot cover all situations where conflicts and dualities may arise in practice.

Keywords:drugpromotion,drugregulation,ethics.

(Aust Prescr 2007;30:150–3)

introductionDespiteimprovementsachievedinthemanagementofcomplex

medicalconditionsinrecentyearsandwidespreadand

increasinguseofpharmaceuticals,thepharmaceuticalindustry

hasbeenincreasinglyportrayedinboththeacademicliterature

andthepopularmediainanunfavourablelight.Whileitmay

betruethattheindustry'snegativereputationisnotcompletely

justified,itisnotdifficulttounderstandthesourceofthe

concerns.

Generalpractitionersandotherhealthprofessionalssuch

aspharmacistsarefrequentlyvisitedbyrepresentativesof

pharmaceuticalcompanies.Thepurposeofthesevisitsisto

promotethecompany'sdrugsandtobuildarelationship.In

dealingwithsuchencounters,situationsmayarisewherethere

isanethicaldilemmaorconflictofinterest.Itisimportant

forhealthprofessionalstobeawareoftheseandtorespond

appropriately.

Drug promotionInAustraliatheprimarytargetsofdrugpromotionaredoctors,

whomaybeprovidedwithgifts,offersoftravel,andother

inducementstoprescribe.1Moresubtlepromotionmayinclude

educationalactivities,drugsamplesanddrugfamiliarisation

schemes,andsupportforthepracticesuchasprovidinganurse

tocollectdata.

Eventhoughdoctorsgenerallydenythattheyareinfluenced

bysuchapproaches2,3,thereisoverwhelmingevidencethat

advertisinginfluencesprescribingbehaviour.Physicians

whoattendpharmaceuticaleventsaremorelikelytousethe

productsofthesponsors,evenintheabsenceofreliableand

credibleevidenceintheirfavour.4,5Promotionalactivitiesin

generalleadtoincreasedprescribingofdrugs,acceptanceof

commercialratherthanscientificviews,apropensitytoengage

innon-rationalprescribingbehaviour6,7,8,andbiasesinfavourof

acompany'sdrugs.9,10

Whileresearchundertakenbyindustryisoftenrigorousand

wellconducted,itmaybedrivenbycommercialimperatives

leadingtobiasedpresentationandinterpretationofresults.11,12

Protocolsandmethodologiesmayreflectandsupportintended

outcomesratherthandisinterestedinquiry.13

Perhapsofevengreaterconcernisthewelldocumentedfact

thatindustryinterestssubstantiallyinfluencethesocialagenda

relatingtotheunderstandingofhealthanddisease,sexuality,

bodyimageandlifestyles.14,15

What is special about drug promotion?Concernabouttheroleandinfluenceofthepharmaceutical

industryisheightenedbecauseofthespecialfeaturesof

medicinescomparedtoothercommercialproducts.The

consumersofmedicationsareoftenextremelyvulnerable,for

theobviousreasonthattheirhealthmaybeatstakeinusinga

product.Decisionsaboutwhatdrugstouseareoftentaken

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 151

notbythemalonebutbytheirmedicalpractitioners,whose

interestsarenotalwaysidenticaltothoseoftheirpatients.

Forprescriptiondrugs,medicalpractitionershavegreat

influenceandarechargedwiththeresponsibilityofbalancing

patients'needsandthepublicinterest.Theyhaveknowledge

andexpertisetoassessthescientificevidence,andaccesstothe

specificcontextualdetailsofmedicalneedinparticularcases.

Forover-the-counterproducts,pharmacistsadvisepatientsand

directlybenefitfrommakingasale.Theymayalsobeoffered

incentivestostockparticularbrands.

Theongoingdebatesabouttheroleandpowerofthedrug

industryinthepopularmedia16,17,18havenodoubtinfluenced

communityattitudes,althoughitisdifficulttodeterminejust

whatimpactthesemayhavehad.Whilesomeconsumer

groupshaveexpressedsuspicionandhostilitytotheindustry,

othergroupshaveemphasisedtheimportanceofimproved

co-operationanddevelopmentofactivecollaborations.19Public

scepticismmayhelptocontroldoctors'dealingswithindustry,

butmayalsodamagethedoctor–patientrelationship.

Physiciansneedtobeawareoftheevidenceabouttheimpact

ofadvertisingonbehaviourandcommunityperceptions.While

bansontheprovisionofinformationbydrugcompaniesare

inappropriate,highlevelsofcriticalawareness,supportedby

educationalprograms,areneededbyclinicians.

Inmanycountries,includingAustralia,thepurchaseof

medicationsisheavilysubsidisedfrompublicfunds.The

prescriberthereforedoesnotdirectlybearthecostoftheir

decisions.

Conflicts of interestsoneofthekeyrequirementsofahealthprofessionalinvolved

ininteractionswithindustryistobeabletodistinguishdualities

andconflictsofinterests.Adualityexistswheretherearetwoor

moresocialrolesthatoverlap,eachofwhichisassociatedwith

amoralimperative.Aconflictexistswheretheseimperatives

arecontradictoryandthreatentocompromisetheprimarygoal

ofoneofthem.

Adualityofinterestwouldexistwhenageneralpractitioner

involvedinresearchisconsideringrecruitingtheirownpatients

forastudy,orwhenadoctorconsidersacceptingtravel

assistancefromapharmaceuticalcompanytoattendameeting

withundisputedscientificcontentatapleasantresortlocation.

Theprinciplesforrespondingtoadualityarestraightforward.

Itneedstobeidentifiedanddisclosedpubliclytotherelevant

community.Thiscommunityshoulddecidewhetherit

constitutesaconflictand,ifso,thisneedstobemanaged,

usuallybydisengagingthetwoconflictingroles.

Sometimesthisprocessofdisengagementisstraightforward

–forexample,ifresearchersproposetoincludetheirown

patientsinaresearchprojecttheyshouldingeneralnot

approachthepatientthemselvesbutleavetheconsentprocess

tothirdparties.onotheroccasions,suchaswherearesearcher

hasdirectpecuniaryinterestsinaproductbeingtested,more

elaboratemechanisms,suchasanarm'slengthcommitteeor

divestmentofshareholdings,maybenecessary.

Regulation of drug promotionInresponsetotherealorperceivedrisksassociatedwiththe

pharmaceuticalindustry'sinfluenceandpower,anarrayof

formalandinformalmechanismsforregulatingtheindustry

hasdeveloped.Theseincluderulessetbygovernment,

industrycodesofconduct,guidelinesgeneratedbypractitioner

associations,processesforthereviewandmanagement

ofresearch,andcommunityresponses.Together,they

seektoensureawiderangeofgoals,includingprotection

oftheinterestsofthecommunityandindividualpatients,

responsivenesstospecificclinicalcontexts,fosteringofresearch

anddevelopmentofnewproducts,maintenanceofpublic

confidenceinpharmaceuticalsandmedicine,facilitationof

ethicaldecisionmakingamongthevariousparticipants,and

enhancementofoptionsandfreedomtoact.

GovernmentAlthoughgovernmentregulationundoubtedlyplaysakey

role,itisabluntinstrumentthatmaynotbeabletoprovide

specificguidanceforallcircumstancesthatoccurinaclinical

setting.Statutoryregulatoryregimesarealsocumbersomeand

bureaucraticandrequireelaborateandexpensivesystemsof

enforcement.

IndustryTheindustryitselfhasdevelopedacodeofconduct,which

isadministeredthroughtheindustrypeakbody,Medicines

Australia.20ThisCodehasbeencriticised,forexample,on

thebasisthatmembershipofMedicinesAustralia,andthus

allegiancetoitspolicies,isvoluntaryanddoesnotincludeall

manufacturers.Areasofconcern,suchasthecollectionand

controlofdata,areomittedaltogether.EnforcementoftheCode

isincompleteandmostlyreliesoncomplaints.Sanctionsfor

breachesaregenerallymodest.21nonetheless,itisbelievedthat

theCoderepresentsasubstantialachievementandthatithas

contributedtosignificantchangeinthecommercialbehaviour

ofthepharmaceuticalindustryinAustralia.Forexample,a

recentamendmenttotheCodenowrequirespharmaceutical

companiestopubliclydisclosethecostofeventsorganisedfor

doctors.

Guidelines for health professionalsAnumberofprofessionalassociationshavedeveloped

guidelinesabouttheethicalrelationshipsbetweenhealth

professionalsandthepharmaceuticalindustry.22,23Amongthese

aretheRoyalAustralasianCollegeofPhysicians(RACP)24,the

RoyalAustralianCollegeofGeneralPractitioners(RACGP)25,and

thePharmaceuticalSocietyofAustralia.26

152 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

RACP recommendationsTheseguidelinesseektodemonstratehowdualitiesmay

bemanagedinspecificcircumstancesthatariseincommon

practice.Theyrecommendthatgiftsshouldberejected,even

itemsoftrivialvalue.Ingeneral,acceptanceoftravelexpensesis

discouraged.However,whereapractitionerismakingaformal

contributiontoameetingitmaybeacceptablefortheorganising

committeetoofferassistancewithtravelandothercosts.

Forscientificmeetingsorprofessionaldevelopmentevents,itis

importantthatprogramsaredevelopedbycommitteesatarm's

lengthfromsponsorsandthatsponsorshipisnotnegotiatedon

thebasisofconditionsrelatingtospeakersorcontent.

TheRACPguidelinescovermanyissuesregardingresearch,

includingdesignofexperiments,managementand

interpretationofdata,andpublicationofresults,whichraise

thepossibilityofconflictsofinterests.Researchershavespecial

responsibilitiestoensurethattheconductandoutcomesof

researcharenotinfluencedbypecuniaryornon-pecuniary

interestsandthatthepubliccanhavefullconfidenceinthe

integrityofanydatathataredisseminated.

RACGP recommendationsTheRACGPmakessimilarrecommendationstogeneral

practitionersbutismorerelaxedaboutdoctorsaccepting

gifts.Agiftmaybeacceptedbutthepatientshouldbethe

primarybeneficiaryandthegiftshouldberelatedtothegeneral

practitioner'swork.So,forinstance,giftssuchasastethoscope

oratextbookareacceptable,whereasgiftsofaholiday,

frequentflyerpoints,acomputerorcashpaymentsarenot

acceptable.

Theguidelinesalsorecommendthatifageneralpractitioner

isinvolvedinpostmarketingsurveillancestudies,theyshould

makeitcleartothepatientthatthepatient'swelfareisnot

dependentonparticipationinthestudyandtheycanwithdraw

atanytimeandstartanalternativetreatmentiftheywish.

The Pharmaceutical Society of Australia CodeAlthoughverybrief,theCodeobligatespharmaciststoavoid

situationsthatmaypresentaconflictofinterest.Accepting

inappropriategiftsisalsocontrarytotheCode.

Conclusionopinionsdifferandcontroversiescontinueabouttheinfluence

ofthepharmaceuticalindustryandtheproperresponses

toit.ThesystemofregulationthathasevolvedinAustralia

iscomplexandheterogeneous,incorporatingcomponents

fromgovernment,industry,communityandtheprofessions.

Althougheachwouldonitsownbeinsufficient,together

theseelementsconstituteadelicatelybalancedequilibrium

thatgoesatleastsomewaytowardsensuringthatthediverse

tasksandgoalssetbythevariousstakeholdersareaddressed

andacknowledged.Whetherthebalanceshouldshiftmorein

thedirectionofregulation,whetheramorepunitiveapproach

wouldbemoreorlesseffective,howbesttomaintainboth

economicincentivesandpublicresponsibility–orevenifitis

possibletodoso–remainsuncertain.

References1. McneillPM,KerridgeIH,HenryDA,StokesB,HillSR,

newbyD,etal.GivingandreceivingofgiftsbetweenpharmaceuticalcompaniesandmedicalspecialistsinAustralia.InternMedJ2006;36:571-8.

2. BrettAS,BurrW,MolooJ.Aregiftsfrompharmaceuticalcompaniesethicallyproblematic?Asurveyofphysicians.ArchInternMed2003;163:2213-8.

3. HalperinEC,HutchisonP,BarrierRCJr.Apopulation-basedstudyoftheprevalenceandinfluenceofgiftstoradiationoncologistsfrompharmaceuticalcompaniesandmedicalequipmentmanufacturers. IntJRadiatoncolBiolPhys2004;59:1477-83.

4. HaayerF.Rationalprescribingandsourcesofinformation.SocSciMed1982;16:2017-23.

5. LexchinJ.Interactionsbetweenphysiciansandthepharmaceuticalindustry:whatdoestheliteraturesay?CMAJ1993;149:1401-7.

6. WazanaA.Physiciansandthepharmaceuticalindustry:isagifteverjustagift?JAMA2000;283:373-80.

7. PeayMY,PeayER.Theroleofcommercialsourcesintheadoptionofanewdrug.SocSciMed1988;26:1183-9.

8. ChrenMM,LandefeldCS.Physicians'behaviorandtheirinteractionswithdrugcompanies.Acontrolledstudyofphysicianswhorequestedadditionstoahospitaldrugformulary.JAMA1994;271:684-9.

9. RutledgeP,CrookesD,McKinstryB,MaxwellSR.Dodoctorsrelyonpharmaceuticalindustryfundingtoattendconferencesanddotheyperceivethatthiscreatesabiasintheirdrugselection?Resultsfromaquestionnairesurvey.PharmacoepidemiolDrugSaf2003;12:663-7.

10. AgrawalS.Pharmaceuticalindustryandsponsorshipofdelegatesfornationalconferences.IndianPediatr2002;39:445-8.

11. HenryDA,KerridgeIH,HillSR,McneillPM,DoranE,newbyDA,etal.Medicalspecialistsandpharmaceuticalindustry-sponsoredresearch:asurveyoftheAustralianexperience.MedJAust2005;182:557-60.

12. HenryD,DoranE,KerridgeI,HillS,McneillPM,DayR.Tiesthatbind:multiplerelationshipsbetweenclinicalresearchersandthepharmaceuticalindustry.ArchInternMed2005;165:2493-6.

13. BeroLA,RennieD.Influencesonthequalityofpublisheddrugstudies.IntJTechnolAssessHealthCare1996;12:209-37.

14. IllichI.Limitstomedicine.London:MarionBoyars;1977.

15. MoynihanR.Themakingofadisease:femalesexualdysfunction.BMJ2003;326:45-7.

16. AngellM.Thetruthaboutthedrugcompanies:howtheydeceiveusandwhattodoaboutit.newYork:RandomHouse;2004.

17. MoynihanR,CassellsA.Sellingsickness:howthedrugcompaniesareturningusallintopatients.Sydney:Allen&Unwin;2005.

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 153

18. JohnleCarre.Theconstantgardener.newYork:SimonandSchuster;2001.

19. Workingtogether.Theguide.Aguidetorelationshipsbetweenhealthconsumerorganisationsandpharmaceuticalcompanies.Consumers'HealthForumofAustraliaandMedicinesAustralia.2005.http://www.chf.org.au/Docs/Downloads/360_guide_for_relationships.pdf[cited2007nov12]

20. MedicinesAustralia.CodeofConduct.15thed.2006.AmendedAug2007.http://www.medicinesaustralia.com.au[cited2007nov12]

21. MedicinesAustraliaCodeofConduct:breaches.AustPrescr2007;30:151-3.

22. BickerstaffeR,BrockP,HussonJM,RubinI,BragmanK,PatersonK,etal.Ethicsandpharmaceuticalmedicine–thefullreportoftheEthicalIssuesCommitteeoftheFacultyofPharmaceuticalMedicineoftheRoyalCollegesofPhysiciansoftheUK.IntJClinPract2006;60:242-52.

23. KomesaroffPA,BachMA,DanoffA,GrumbachMM,KaplanS,LakoskiJM,etal.TheEndocrineSocietyEthicsAdvisoryCommittee:ethicalaspectsofconflictsofinterests,october2003.Endocrinology2004;145:3032-41.

24. KomesaroffP,CarneyS,LaBrooyJ,TattersallM,GreenbergP.Guidelinesforethicalrelationshipsbetweenphysiciansandindustry.3rded.Sydney:RoyalAustralasianCollegeofPhysicians;2006.http://www.racp.edu.au[cited2007nov12]

25. RoyalAustralianCollegeofGeneralPractitioners.Generalpractitionersandcommercialsponsorship.http://www.racgp.org.au/guidelines[cited2007nov12]

26. PharmaceuticalSocietyofAustralia.Giftsfrompharmaceuticalcompanies.http://www.psa.org.au[cited2007nov12]

Conflict of interest: none declared

Dental notesPrepared by Dr M McCullough of the Australian Dental Association

Relationships between health professionals and industry: maintaining a delicate balanceThelevelofprescribingthatoccursintheaveragedentalpractice

isnotusuallysuchthatitattractstheattentionofpharmaceutical

companies'marketingdepartments.However,wearelarge

consumersofrestorativematerials,medicamentsandother

products.Werelyonagoodworkingrelationshipwithdental

supplycompanieswhonotonlyofferaccesstotheseproducts,

butarealsoofteninvolvedinresearchrelatedtothem.Itismost

likelythatdentistsarenotawareoftheinfluencethatadvertising,

'specialoffers',personalvisitsbycompanyrepresentatives,

endorsementsandtradeshowshaveonourpurchasinghabits.

Whatdentalpractitionerspurchaseorprescribeshouldalways

bedoneonthebasisofavailablescientificevidencewith

patients'interestutmostinourminds.Infact,inthemajority

ofpracticesitisnotthedentistswhopurchasetheseitems,but

ratherthepracticemanagerontheadviceofthedentist,advice

thatmaynotbeconsistentlyavailable.Situationsofconflict

anddualityofinterestmaywellberelativelycommoninthe

dentalprofession,andtheseshouldbeacknowledgedand

dealtwithinanopenmanner.Currently,theAustralianDental

Associationisdevelopingapolicytoadviseitsmemberswhere

theseconflictsanddualitiesofinterestsarise.

MedicinesAustraliahasaCodeofConducttoguidethe

promotionofprescriptiondrugsbypharmaceuticalcompanies

inAustralia.AneweditionoftheCodehasrecentlybeen

approved.1ComplaintsareconsideredbytheCodeofConduct

Committeeandtheresultsarepublishedinitsannualreport.

Thereportfor2006–07isavailableontheMedicinesAustralia

website.2

Thisyear'sreportcontainsdetailedinformationabout41

complaints.InfourteencasesnobreachoftheCodewasfound.

Table1showsthe27complaintsinwhichatleastonebreach

oftheCodewasfound.Asusual,mostofthecomplaintswere

madebyrivalpharmaceuticalcompanies,but12weremadeby

healthprofessionals.

Mostofthebreacheswereforusingmisleadinginformationin

promotionalmaterial.Someofthelargerfineswereimposed

oncompaniesthathadallowedthepublictobeexposed

totheirpromotions.Twocomplaintsrelatedtoacompany

whichsponsoredthenationalconferenceofapatientsupport

Medicines Australia Code of Conduct: breaches

154 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

group.Anarticle,originallydraftedforhealthprofessionals,

butpublishedinReader'sDigest,clearlybreachedtheCode.

Anotherbreach,identifiedbyseveralcomplaints,wasoffering

a'money-backguarantee'topatientsbeingtreatedforerectile

dysfunction.

Theinformationinthereportrevealssomeofthesophisticated

strategiescompaniescanuse.onecompanyhadusedapublic

relationsconsultanttomanageacampaignaboutamedicine

whichhadyettobeapprovedinAustralia.Thisincluded

sponsoringajournalisttoattendanoverseasconferenceabout

thedrug.Issuingamediareleaseonanunapproveddrugwas

consideredtobepromotionalactivitywhichbreachedtheCode.

TheCommitteehadtograpplewithwhatconstitutesexcessive

The story of one complaintJohn S Dowden, Editor

Anadvertisingcampaignforvardenafilencouragedmen

witherectiondifficultiestoseektreatment.Theadvertisement

includedtheproductlogoandthenameofthecompany.

Theimagery,ofanuprightbanana,wasalsousedinthe

advertisingtohealthprofessionals.Aspartofthisparallel

campaign,doctorsandpharmacistswereinformedthatthe

companywouldofferamoney-backguaranteetopatients.

ImadeacomplainttoMedicinesAustraliaasIbelievedthat

theadvertisingtothepublicwouldstimulatedemandfora

particularproductandthemoney-backguaranteecouldbe

seenasaninducement.Complaintswerealsomadebytwo

pharmacistsandtheAustralianConsumers'Association.

TheCodeofConductCommitteeconsideredmycomplaint

withinamonthandsentmeitsdecisionwithinsixweeks.The

rulingwasinanextractoftheminutesoftheCommittee's

meeting.Thisshowedthattherehadbeenaseverebreach

oftheCodeofConduct,butIwasaskedtokeeptheruling

confidentialincasetherewasanappeal.Astherewasno

hospitality.onecompanywasfinedforprovidingafunction

thatwasnot'simpleormodest',whileafunctionattheCrown

TowersinMelbournewasruledtobe'notextravagant'.Perhaps

thenewrequirementforcompaniestodisclosethecostoftheir

promotionalfunctionswillhelptheCodeofConductCommittee

decidewhatisappropriate.

References1. MedicinesAustralia.CodeofConduct.15thed.2006.

AmendedAug2007.http://www.medicinesaustralia.com.au[cited2007nov12]

2. MedicinesAustraliaCodeofConductAnnualReport2006/2007.Canberra:MedicinesAustralia;2007.http://www.medicinesaustralia.com.au[cited2007nov12]

appealthecomplaintwasfinalisedanddetailsappearinthe

CodeofConductAnnualReport.1

TheCodeofConductCommitteeconsideredthatthe

advertisingcampaigncouldhavebreachedninesectionsofthe

Code,howeveronlyonebreachwasconfirmed.Amajorityof

theCommitteeconsideredthatthecampaignbroughtdiscredit

totheindustry.Thiswasnotbecausethebananaimages

wereinpoortaste,butbecauseamoney-backguaranteewas

consideredtodecreasethevalueofprescriptionmedicines.

TheCodeofConductCommitteedidnotfinethecompany

fortheseverebreach,butorderedittoimmediatelycease

thepromotionofferingthemoney-backguarantee.Corrective

lettershadtobesenttoallhealthprofessionalswhoreceived

thepromotionandcorrectiveadvertisementshadtobe

placedinhealthprofessionaljournalswhichhadpublished

advertisementsaboutthemoney-backguarantee.

Reference1. MedicinesAustraliaCodeofConductAnnualReport

2006/2007.Canberra:MedicinesAustralia;2007.http://www.medicinesaustralia.com.au[cited2007nov12]

Table 1

breaches of the Code of Conduct July 2006 – June 2007

Company Drug Sanction imposed by Code of Conduct Committee

brand name generic name

AbbottAustralasia Lucrin leuprorelin WithdrawmaterialCorrectiveletter$10000fine

AlconLaboratories DuoTrav timololmaleate/travoprost

Ceaseprogram$10000fine

AllerganAustralia Lumigan bimatoprost WithdrawmaterialCorrectiveletter$15000fine

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 155

AstraZeneca Crestor rosuvastatin WithdrawpromotionalmaterialsCorrectiveletter$75000finereducedonappealto$40000

nexium esomeprazole Withdrawmaterials$75000fine

BayerHealthcare Levitra

(fourcomplaints)

vardenafil Withdrawmoney-backguaranteeofferCorrectivelettersCorrectiveadvertisement

BoehringerIngelheim Buscopan hyoscine Withdrawmaterial$25000finereducedonappealto$10000

Mobic meloxicam WithdrawmaterialsCorrectiveletter$25000fine

CSLLimited Biostate factorVIII $5000finedroppedonappeal

Behaviourofcompanyrepresentative Withdrawtrainingmaterial$15000fine

GlaxoSmithKlineAustralia

Rotarix rotavirusvaccine WithdrawmaterialsCorrectiveletter$25000fine

Tykerb lapatinib Providenomediareleasesuntilmedicineregistered$40000fine

Janssen-Cilag Pariet rabeprazole Withdrawmaterial$100000fine

Pariet rabeprazole Withdrawmaterialothersanctionscoveredinpreviousbreach

MerckSharp&Dohme FosamaxPlus alendronate Withdrawmaterials

octapharma octanate factorVIII WithdrawmaterialsCorrectiveletter$100000finereducedonappealto$10000

PfizerAustralia Celebrex celecoxib Withdrawmaterials$100000fine

Celebrex celecoxib Articlenottobepublishedagainforgeneralpublic$100000fine

Xalacom latanoprost/timololmaleate

WithdrawmaterialCorrectiveletter$50000fine

RocheProducts Hospitality $75000fine

Sanofi-Aventis Stilnox zolpidem Withdrawmaterials

$5000fine

Schering Betaferon interferonbeta-1b Withdrawmaterials

Correctiveletters

$150000fine

Betaferon interferonbeta-1b Withdrawmaterials

LettertoMultipleSclerosisSociety

$100000fine

Angeliq drospirenone/oestradiol

Ceasedistributionoftradepacks

156 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

Treatment of myasthenia gravisStephen W Reddel, Sydney Neurology, Brain and Mind Research Institute, The University of Sydney, and Departments of Neurology and Molecular Medicine, Concord Repatriation General Hospital, Sydney

Summary

Myasthenia gravis is a syndrome of weakness and fatigue due to dysfunction of the neuromuscular junction. it is an antibody-mediated autoimmune condition with a range of moderately effective treatments. occasionally patients go into remission spontaneously, but most require treatment. Mild disease, such as that confined to the ocular muscles, can often be treated with pyridostigmine alone. More significant or generalised weakness requires immunosuppression, principally with prednisone and azathioprine. The response to immunosuppression is slow, ranging from several months to 1–2 years for a full response. Short-term use of antibody-based therapy such as plasma exchange or intravenous immunoglobulin is warranted for more severely affected patients. Thymectomy offers the hope of drug-free remission but as yet remains unproven. Treatment-related morbidity is considerable, but partly preventable.

Keywords:azathioprine,immunosuppression,prednisone,

pyridostigmine,thymectomy.

(Aust Prescr 2007;30:156–60)

introductionMyastheniagravisisanautoimmunediseasewhichcauses

muscularweaknessduetodysfunctionoftheneuromuscular

junction(Fig.1).Autoantibodiesdirectedagainstantigenic

proteinsonthepostsynapticsideoftheneuromuscularjunction

resultinbothblockadeoftransmissionanddamagetothe

postsynapticstructure.Asaresultthemotorneuronisunable

to'talk'tothemusclefibreandweaknessresults.Theknown

antigenstowhichtheautoantibodiesbindaretheacetylcholine

receptorand,lesscommonly,muscle-specifictyrosinekinase.

Theprevalenceofmyastheniagravisisabout1in10000.The

genderratioisapproximatelyequal,withapeakincidenceof

onsetinthe20sforwomenandthe60sformen.Around10%

ofpatientswithapositiveacetylcholinereceptorantibodytest

haveanassociatedthymoma.

DiagnosisTherearearangeofdiagnostictestsformyasthenia

gravis.Theseincludedynamictestsformeasuringmuscle

weakness(forexample,responsetoedrophoniumorice

pack),electricaltestssuchasrepetitivestimulationorsingle

fibreelectromyography,andmeasurementofantibodiesto

acetylcholinereceptorandtomuscle-specifictyrosinekinase.

Clinical manifestationsMyastheniagravisaffectssomeregionalmusclesmorethan

others.Mostcommonlytheorbitalmusclesareaffectedfirst,

witheitherdiplopiaorptosis.However,myastheniagravismay

firstaffectthebulbarmuscles(speechandswallowing),the

neckmuscles(headdrops)andproximalorrarelydistallimbor

respiratorymuscles.Involvementisfairlysymmetricalexcept

intheeyes.Symptomsmaygetworsetowardstheendofthe

dayorafterafewminutesofcontinuoususe–forinstance

speechmaybecomeslurredoverafewminutes.Moresevere

myastheniagravisaffectsmultiplemuscularregionsandmay

besufficientlyseveretocauserespiratoryfailureanddeathif

untreated.

Natural history of myasthenia gravisGenerally,myastheniagravisisapersistentdiseaserequiring

chronictreatment.Fluctuationsoverthelongtermarethenorm.

Somepatientsgointolong-termremissionspontaneously–

approximately15–25%afterfiveyearsforthosepresentingwith

generaliseddiseaseandsomewhatmoreforthosepresenting

withoculardiseaseonly.Laterelapseaftersustainedremission

alsooccurs,thelongestreportedexamplebeingafter32years.

Itshouldbenotedthattheneuromuscularjunctioncanbe

reformed,unlikemanypartsofthenervoussystem.Muscle

strengththathasbeenaffectedbymyastheniagravisforalong

timeoftenrecoverswithtreatment.Thismeansthattheintensity

oftreatmentformyastheniagraviscanbemodulatedtothe

currentseverityofthedisease.

overtime,patientswithclinicallyisolatedocularmyasthenia

gravisoftenprogresstogeneralisedmyastheniagravis.

Treatmentwithcorticosteroidscanreducethelikelihoodof

progression,andcontrolbothocularandgeneralisedweakness

completelyinmanycases.Itisnotknownifthisaltersthe

naturalhistoryortheneedforlong-termtreatment.Itis

thereforeunclearwhethertreatmentshouldbecommencedfor

oculardiseaseorjust'asrequired'tocontrolsymptomsthat

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 157

arecausingsufficientdisabilitytojustifytheadverseeffectsof

treatment.Long-standingocularmisalignmentmaynotrecover

despitegeneralisedremission.

Treatment Thediagnosismustbeconfirmedbeforetreatment,becausethe

mainstayoftreatmentformostpatientsisimmunosuppression.

Treatmentstopreventtheadverseeffectsof

immunosuppressionshouldbestartedsimultaneouslywiththe

therapy(seeTable1).Thereisnorobustevidencethatlong-term

treatmentactuallycuresthecondition,sosomepatientschoose

toavoidtheadverseeffectsofimmunosuppressivetherapy

andacceptdegreesofweakness.Copingwithouttreatment

isnotalwaysthesafeststrategyaspatientswithsignificant

weakness,particularlyinthebulbarmusculature,areatrisk

ofventilatoryfailureorofneedingintensivecarefollowingan

intercurrentrespiratoryinfection.Immunosuppressivetreatment

isthereforestronglyrecommendedforcontrolofsignificant

bulbarweakness.

Initialtreatmentisusuallywithpyridostigmine,followedby

prednisoneandazathioprineiftheresponseisincomplete.A

combinationofapproachesisoftenusefultocoverdeficiencies

ineachavailabledrug.

Immunosuppressionproducesaveryslowresponse,often

takingmanymonthsto1–2years.1,2Anunrealisticexpectation

ofaspeedyresponseisoftenaproblemforboththepatientand

thedoctor.

Therearefourmainapproachestotreatment,eachwithvery

differentdurationsofeffect,requirements,consequencesand

adverseeffects.

Improve neuromuscular transmission by inhibiting acetylcholinesterase Drugsthatinhibitacetylcholinesteraseincludepyridostigmine,

edrophonium(usedonlyfortesting)andneostigmine(for

intravenoususeinintensivecareunitsonly).Thesedrugs

takeeffectwithinminutesandlastforhours.Althoughthey

arewithoutlong-termadverseeffects,theefficacyofall

Fig. 1

Normal muscular junction

Inthenormalneuromuscularjunction,acetylcholinereleasedfromthenerveterminalfollowinganerveactionpotential,

bindstotheacetylcholinereceptoronthepostsynapticmuscle,triggeringamuscleactionpotentialpropagatedbythe

voltagegatedsodiumchannel.Acetylcholinesterasescavengesandbreaksdownunboundacetylcholine.Inaseparate

pathway,neuralagrinbindsmusclespecifictyrosinekinaseinitiatingclusteringofphosphorylatedrapsynandacetylcholine

receptors,stabilisingthepostsynapticstructureoppositethenerve.

Inmyastheniagraviscausedbyantibodiestotheacetylcholinereceptor,thereisblockadeofthebindingsitefor

acetylcholine,cross-linkingoftheacetylcholinereceptorwithsubsequentinternalisationandreductioninitssurface

expression,andinitiationofcomplementandcellularinflammatorycascadeswithdamagetothepost-andpresynaptic

structures.Themolecularphysiologyofmyastheniagravismediatedbyantibodiestomusclespecifictyrosinekinasehas

notbeenestablished.

acetylcholine

agrin

acetylcholineinapresynapticvesicle

nicotinicacetylcholinereceptor

musclespecifictyrosinekinase

rapsyn

voltagegatedsodiumchannel

acetylcholinebindingsite

acetylcholinesterase

Nerve terminal

Muscle fibre

158 | VoLuME 30 | NuMbER 6 | DECEMbER 2007

acetylcholinesteraseinhibitorsislimited.Asasoledrugthey

arenotenoughformostpatientswithgeneralised

myastheniagravis.

PyridostigminePyridostigmineisthefirst-linetreatmentformyasthenia

gravis.Itisareversibleinhibitorofacetylcholinesterase

soincreasesacetylcholinestimulationoftheremaining

acetylcholinereceptors.Ifthereareinsufficientacetylcholine

receptorsremainingtotriggeramuscleactionpotential,extra

acetylcholinefromtheactionofthedrugisnotgoingtohelp.

Theunderlyingautoimmunestateisnotaltered.Itisoften

sufficientforptosisalone,butnotfordiplopiaorgeneralised

myastheniagravis.Benefitisoftennotsustained,possiblydue

tocounterproductiveupregulationofacetylcholinesteraseand

downregulationofacetylcholinereceptors.Thedoserequiredis

variable,asisgastrointestinaltolerance.oneapproachistostart

at10mgthreetimesadayandtitrateupto60mg4–6times

daily.A180mg'timespan'preparationisavailablefornocturnal

symptoms.Inpracticeadegreeofpatientcontrolofdosingand

'whenrequired'useisoftenhelpful.

Doseslessthan480mgdailyrarelyproducedepolarisingcrisis.

Increasingweaknessafteranincreaseinthepyridostigmine

dose(whenhighdosesarealreadybeinggiven)suggests

deterioratingdiseaseand/oradepolarisingcrisis.Thismay

requiretreatmentssuchasplasmaexchangeandareductionin

pyridostigminedose.Thepresenceofgastrointestinaladverse

effectsandfasciculations,clinicallyoronelectromyogram,

mightsuggestdepolarisingcrisis.Thepatientmustbe

hospitalisedandthedoseofpyridostigminereducedwhile

theyarecarefullymonitored.Lackofimprovementwith

edrophonium(whichhasaveryshorthalf-life)indicatesthat

furtherpyridostigminewillnotbeuseful.

ImmunosuppressionTheprincipaldrugsusedtosuppresstheimmunesystem

inmyastheniagravisareprednisone(aglucocorticoid)and

azathioprine.Theresponsetothesetreatmentscantakeweeksto

manymonths,withthemaximaleffecttakingmonthstoyears.1,2

PrednisonePrednisoneoranothercorticosteroidistheprimary

immunosuppressantusedinmyastheniagravis.Sustained

improvementorremissioncanbeachievedwhilepatients

remainontreatment.Atypicalcourseforgeneralised

myastheniagraviswoulduse1mg/kgprednisonedaily

(0.5mg/kgforocularmyastheniagravis)untilclinicalcontrol

isachievedandthenweaningeitherdirectlyorbyinitial

conversiontoalternatedailydosage,withthedeterminationof

amaintenancedosebytrialanderrorduringaslowwithdrawal

ofmedicationovermanymonths.Deteriorationinmyasthenia

graviscanoccurinthefirstfewweeksoftreatmentsothedose

isoftenincreasedslowly.Themeantimetomaximaleffectof

prednisoneinmyastheniagravisissixmonths–muchlonger

thanmostexpect.

AzathioprineAzathioprineisusedasasteroidsparingdrugandadditional

immunosuppressantwithprednisone.Inarandomisedtrial,

afterthreeyearsoftreatment,63%ofpatientswithmyasthenia

gravistakingazathioprinewereoffallprednisone,versus

20%takingplacebo,butnoeffectwasseeninthefirstyear.2

Comparedtothemetabolicconsequencesofcontinued

corticosteroids,theproblemsofazathioprineseemsignificantly

less.However,thelong-termconsequencesdoincludean

increasedriskofskincancersandasmallpossibleincrease

intheriskofhaematologicalmalignancies.Aboutone-fifth

Table 1

Prophylaxis of the complications of immunosuppression

osteoporosisprevention Measurebonedensitybeforetreatmentandyearlywhileontreatment.StartcalciumandvitaminDsupplements.Bisphosphonatesmayreducebonelossassociatedwiththechronicuseofglucocorticoids.

Cardiovascularrisk Riskfactormodificationshouldbestandardandincludesadvicetostopsmoking,startanexerciseprogramandmanagehypertension.

Pepticulcerprevention HelicobacterscreeningandprophylactictreatmentwithprotonpumpinhibitorsorH2antagonistsseemsappropriateforthosewithapasthistoryofpreviousulcerationorconcordantuseofnon-steroidalanti-inflammatorydrugs.

Infectionprophylaxis Useofinactivatedvaccinessuchasinfluenzaisrecommended.Livevaccinesarecontraindicated.AchestX-rayshouldbeperformedpriortotreatment.MorespecifictestingfortuberculosismaybeindicateddependingonhistoryandchestX-rayresults.

Malignancyprevention Skincancerratesareincreasedinpatientsusingazathioprine.Afullyearlydermatologicalsurveyisrecommended.Exhortsunprotectionandcancersurveillance.Regularcervicalsmearsarerecommended.Eyeprotectionmayalsolimitcataractdevelopment.

| VoLuME 30 | NuMbER 6 | DECEMbER 2007 159

ofpatientscannottakeazathioprineduetorash,hepatitis,

myelosuppression,nauseaorvomiting,butthisisusually

evidentwithintwoweekstotwomonths.Somedoctors

routinelyuseazathioprineforpatientswithgeneralised

myastheniagravisstillrequiringmorethan10mgprednisone

perdayatsixmonths,orifseverediseaseisobviousearlier.

Other drugsIfnotusingazathioprine,othersteroid-sparingdrugsused

includemycophenolatemofetil,cyclosporin,methotrexateand

cyclophosphamide.Experiencewiththesedrugsisgenerally

derivedfromretrospectiveseries.noneofthesehaveproven

efficacyinrandomisedtrialsexceptforcyclophosphamide,and

choiceofdrugdependsonageandcompetencyofthepatient

pluslocalexperienceofthephysician.Inpracticetheyare

frequentlyusedwithapparentsuccess,butlikeazathioprinethe

responseisoftenslow.

Mycophenolatemofetilisapharmacologicallysimilar

alternativetoazathioprinebuttworecentrandomisedcontrolled

trialsfailedtodemonstratebenefitinmyastheniagravis.*The

durationofbothtrialswaslessthanayear.Asitworksinthe

samepathwayasazathioprinethismayhavebeeninadequate

anditremainswidelyused.

Rituximab,amonoclonalantibodyspecifictoCD20(onBcells),

orbonemarrowablationwithautologoustransplantare

treatmentsoflastresort.

Remove or block autoantibodies Plasmaexchangeremovesautoantibodiesandintravenous

immunoglobulinisthoughttoblockautoantibodies.These

treatmentstakeeffectwithindays,butonlylastweeksbefore

treatmentneedstoberepeated.Theyhaveakeyrolein

stabilisingseveremyastheniagravisandinpreparationfor

surgery,orinpregnancy.

Plasmaexchangeisexpensiveandonlyavailableinmajor

hospitals.Itrequiresgoodintravenousoralternativelycentral

catheteraccess,butacentrallineincreasestheriskofinfection.

Intravenousimmunoglobulin,apurifiedbloodproduct,isalso

veryexpensiveandisinlimitedsupply.Itsmodeofaction

remainsunclear.

ThymectomyThymectomyhasapossibleimmunomodulatoryroleinthe

absenceofthymoma.Resultsofaglobalrandomisedtrial

areawaited.†Theeffectofathymectomyappearstotake

years.non-randomisedretrospectivedatasuggestthereisan

increasedcompleteremissionratefromthymecto